HL073996, Project 1 (Martin, TR and Wurfel, MM): The major scientific goals of this project are to determine the molecular mechanisms controlling inter-individual variability in inflammatory responses to bacterial products, to characterize the role of specific genes in determining this variability, and to determine whether nucleotide variability within these genes explains a portion of the variability seen in the clinical syndromes such as sepsis and ALI/ARDS. Studies in Aim 1 use oligonucleotide arrays and proteome-level analysis to determine differences in gene and protein expression between normal individuals who show "hyper" and "hypo"-responsive (lpshigh and lpslow) cytokine responses to LPS ex vivo; Aim 2, a classical twins study to estimate the heritable and environmental components to LPS-induced cytokine responses; Aim 3 tests for association between SNP haplotypes within putative LPS-response genes and the ex vivo cytokine responses; In Aim 4, SNP haplotypes within LPS-response genes identified as being associated with the inflammatory response in Aim 3 will be tested in a clinical population of patients with sepsis and ALI/ARDS for association with clinical outcomes.

AI057141, Project 11 (Martin, TR and Wurfel, MM): The major scientific goal of this proposal is to identify the factors that determine human innate immune responses to bacterial bioweapons agents. Aim 1 measures the variability in innate immune responses to Y. pestis and other potential bioweapons agents using an in vitro model of whole blood responses to bacterial products; Aim 2 investigates the magnitude of the genetic component of this variability through a classical twins study; Aim 3 studies are to determine the extent to which specific allelic haplotypes contribute to this variability; Aim 4 will identify innate immune response profiles in patients with chronic respiratory diseases, a population that is likely to be at high-risk for poor outcomes in the event of exposure to aerosolized Y. pestis and other bioweapons agents.